Biology subjects

Peralta Ramos, J. M.

Publications and source records attributed to Peralta Ramos, J. M..

4 recordsLinked to original sources

bioRxiv2026

Disruption of the Brain-Spleen Axis Impairs Monocyte-Microglia Communication and Accelerates Disease Progression in a Model of Amyloidosis

Alzheimers disease (AD) is characterized by a prolonged asymptomatic phase before cognitive decline emerges, yet the mechanisms driving symptom onset remain unclear. Here, we hypothesized that the transition from asymptomatic to symptomatic disease is linked to dysfunction of brain-immune communication. Retrograde neuronal tracing in the 5xFAD mouse model of amyloidosis revealed reduced brain-spleen connectivity at advanced disease stages. To probe the functional role of the brain-spleen axis in coping with disease, we denervated the splenic nerve at an early presymptomatic stage. This intervention accelerated cognitive decline, impaired splenic hematopoiesis, diminished monocyte recruitment to the brain, disrupted monocyte-microglia signaling networks, and reduced the transition of microglia from a homeostatic to the disease-associated (DAM) state. Conversely, enhancing splenic noradrenergic input increased hematopoiesis, restored monocyte homing to the brain, and delayed cognitive impairment. The protective role of splenic monocytes was independently validated in a retinal cytotoxic injury model, in which splenic denervation impaired post-insult retinal ganglion cell survival. Together, these findings identify an active brain-spleen circuit in regulating monocyte recruitment and establish peripheral monocytes as key drivers of microglial state transitions and disease progression.

neuroscience↗

bioRxiv2023

TREM2-dependent senescent microglia conserved in aging and Alzheimer's disease

Dementia in general, and Alzheimers disease (AD) in particular, are age-related diseases1,2. AD is associated with multiple causative factors3,4, among which local brain inflammation plays a significant role5. Microglia, the brain-resident immune cells6,7, are activated along the disease course7. Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor8,9. A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

neuroscience↗

bioRxiv2020

Systemic sterile induced-co-expression of IL-12 and IL-18 drives IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain.

The development of neuroinflammation, as well as the progression of several neurodegenerative diseases, has been associated with the activation and mobilization of the peripheral immune system due to systemic inflammation. However, the mechanism by which this occurs remains unclear. Herein, we addressed the effect of systemic, endotoxin-free induced-co-expression of IL-12 and IL-18 in the establishment of a novel cytokine-mediated model of neuroinflammation. Following peripheral hydrodynamic shear of IL-12 plus IL-18 cDNAs in C57BL/6 mice, we induced systemic and persistent level of IL-12, which in turn promoted the elevation of circulating pro-inflammatory cytokines TNF- and IFN-{gamma}, accompanied with splenomegaly. Moreover, even though we identified an increased gene expression of both TNF- and IFN-{gamma} in the brain, only TNF- was shown to be dispensable, revealing an IFN-{gamma}-dependent activation of microglia and the recruitment of leukocytes, particularly of highly activated inflammatory monocytes. Taken together, our results argue for a systemic cytokine-mediated establishment and development of neuroinflammation, having identified IFN-{gamma} as a potential target for immunotherapy.

immunology↗

bioRxiv2017

Alpha-synuclein fibrils induce autophagy in microglial cells as a consequence of lysosomal damage.

Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. In Parkinsons disease, the synaptic protein alpha-synuclein (AS) accumulates in neuronal cell bodies and axons. Recent studies indicate that aggregation-prone proteins can spread to other brain cells - such as glia - contributing to progressive deterioration.\n\nAlthough autophagic dysfunction and protein aggregation have been linked to several neurodegenerative disorders, exact mechanisms are not clear and most work was done in neurons and not on microglial cells.\n\nHere we report that AS fibrils but not monomers induce lysosomal damage and autophagy in microglial cells and we extensively characterized the dynamics of this response by both live-cell imaging and correlative light-electron microscopy (CLEM). In addition, we found that autophagy inhibition in these cells impairs mitochondrial quality and leads to microglial cell death. We propose that AS accumulation in lysosomes leads to lysosomal damage, which in turn activates canonical autophagy as a rescue mechanism.\n\nOur results provide novel findings about the interaction between AS and the autophagy pathway in microglial cells, which may be important for targeting protein misfolding-associated neurodegenerative diseases.

cell biology↗